Due to their highly vascular nature and high level of vascular permeability factor or vascular endothelial growth factor (VPF/VEGF) expression, clear-cell renal cell carcinoma (RCC) patients show initial success with anti-VEGF therapy. Unfortunately, the majority of patients eventually develop a refractory response to anti-VEGF therapy over time. In this regard, we would like to develop unique treatment strategies for nonresponsive, highly aggressive tumor types to overcome the current clinical challenges. Concurrently, we would like to understand the molecular mechanism of these untreatable tumor types by utilizing patient samples and also using different genetic approaches. We postulate that the proposed experimental plan will be helpful to design new treatment options for lasting anti-angiogenic effects and better clinical management. In addition, we will work on sarcomatoid variant renal cell carcinoma (sRCC), a spindle cell phenotype with a poor prognosis due to a modest or non-response to systemic therapy. To address our objectives, we have developed the following Specific Aims. Aim 1 will examine whether targeted inhibition of VEGF and NRP-1 expression by using novel U1 Adaptor of the respective genes in tumor cells can block metastasis and overall tumor growth and override the anti-VEGF refractory phenotype. Aim 2 will examine whether we can override anti-VEGF resistance by using a VEGFR3 blocking antibody in a preclinical model. We will also evaluate whether U1 Adaptor technology in combination with the VEGFR3 antibody will be more effective in the preclinical setting. Finally, Aim 3 will focus on developing customized therapy against sRCC by utilizing U1 Adaptor-mediated targeting agents and we will also validate some of the data using patient samples. Overall, the proposed experiments will provide new and important information on the mechanisms of carcinogenesis and suggest new targets for intervention in anti-VEGF therapy resistant cRCC and sRCC.